tbuckley/cabot-search huggingface dataset:
The Cytidine Deaminase APOBEC3G Contributes to Cancer Mutagenesis and Clonal Evolution in Bladder Cancer
Authors: Weisi Liu, Kevin P. Newhall, Francesca Khani, LaMont Barlow, Duy Nguyen, Lilly Gu, Ken Eng, Bhavneet Bhinder, Manik Uppal, Charlotte Récapet, Andrea Sboner, Susan R. Ross, Olivier Elemento, Linda Chelico, Bishoy M. Faltas
Journal: Cancer Research (2022)

Abstract Mutagenic processes leave distinct signatures in cancer genomes. The mutational signatures attributed to APOBEC3 cytidine deaminases are pervasive in human cancers. However, data linking individual APOBEC3 proteins to cancer mutagenesis in vivo are limited. Here, we showed that transgenic expression of human APOBEC3G promotes mutagenesis, genomic instability, and kataegis, leading to shorter survival in a murine bladder cancer model. Acting as mutagenic fuel, APOBEC3G increased the clonal diversity of bladder cancer, driving divergent cancer evolution. Characterization of the single-base substitution signature induced by APOBEC3G in vivo established the induction of a mutational signature distinct from those caused by APOBEC3A and APOBEC3B. Analysis of thousands of human cancers revealed the contribution of APOBEC3G to the mutational profiles of multiple cancer types, including bladder cancer. Overall, this study dissects the mutagenic impact of APOBEC3G on the bladder cancer genome, identifying that it contributes to genomic instability, tumor mutational burden, copy-number loss events, and clonal diversity. Significance: APOBEC3G plays a role in cancer mutagenesis and clonal heterogeneity, which can potentially inform future therapeutic efforts that restrict tumor evolution. See related commentary by Caswell and Swanton, p. 487
Improved survival and MRD remission with blinatumomab vs. chemotherapy in children with first high-risk relapse B-ALL
Authors: Franco Locatelli, Gerhard Zugmaier, Carmelo Rizzari, Joan D. Morris, Bernd Gruhn, Thomas Klingebiel, Rosanna Parasole, Christin Linderkamp, Christian Flotho, Arnaud Petit, Concetta Micalizzi, Yi Zeng, Rajendra Desai, William N. Kormany, Cornelia Eckert, Anja Möricke, Mary Sartor, Ondrej Hrusak, Christina Peters, Vaskar Saha, Luciana Vinti, Arend von Stackelberg
Journal: Leukemia (2022)
Mitochondrial DNA Mutations as Natural Barcodes for Lineage Tracing of Murine Tumor Models
Authors: Livius Penter, Elisa ten Hacken, Jackson Southard, Caleb A. Lareau, Leif S. Ludwig, Shuqiang Li, Donna S. Neuberg, Kenneth J. Livak, Catherine J. Wu
Journal: Cancer Research (2022)

Murine models are indispensable tools for functional genomic studies and preclinical testing of novel therapeutic approaches. Mitochondrial single-cell assay for transposase-accessible chromatin using sequencing (mtscATAC-seq) enables the dissection of cellular heterogeneity and clonal dynamics by capturing chromatin accessibility, copy-number variations (CNV), and mitochondrial DNA (mtDNA) mutations, yet its applicability to murine studies remains unexplored. By leveraging mtscATAC-seq in novel chronic lymphocytic leukemia and Richter syndrome mouse models, we report the detection of mtDNA mutations, particularly in highly proliferative murine cells, alongside CNV and chromatin state changes indicative of clonal evolution upon secondary transplant. This study thus demonstrates the feasibility and utility of multi-modal single-cell and natural barcoding approaches to characterize murine cancer models.mtDNA mutations can serve as natural barcodes to enable lineage tracing in murine cancer models, which can be used to provide new insights into disease biology and to identify therapeutic vulnerabilities.
Preoperative Neutrophil-to-Lymphocyte Ratio and a New Inflammatory Biomarkers Prognostic Index for Primary Retroperitoneal Sarcomas: Retrospective Monocentric Study
Authors: Marco Fiore, Silva Ljevar, Sandro Pasquali, Daniele Morelli, Dario Callegaro, Roberta Sanfilippo, Marta Barisella, Claudia Sangalli, Rosalba Miceli, Alessandro Gronchi
Journal: Clinical Cancer Research (2022)

Inflammatory biomarkers and neutrophil-to-lymphocyte ratio (NLR) are associated with prognosis in several tumors. Data on sarcomas are limited, and insufficient on retroperitoneal sarcoma (RPS). Patients with primary RPS operated between 2002 and 2016 were included. Hemoglobin, monocytes, NLR, platelet-to-lymphocyte ratio (PLR) were retrieved and analyzed both individually and combined into a prognostic index (IBPI). Correlation with clinicopathologic variables was studied, as well as postoperative morbidity according to NLR and IBPI risk categories. The association between overall survival (OS) and biomarkers and, in addition, the 7-year Sarculator-predicted OS probability (pOS) was analyzed using univariable and multivariable Cox models. 423/463 patients had complete data. The median follow-up was 84 months. The median NLR was 3.3 (IQR, 2.4-4.7), with significant variation across histologies. NLR was the only biomarker that independently predicted OS (HR, 1.2; 95% CI, 1.03-1.40; P = 0.02). The IBPI showed good discrimination for subgroups at different OS (log-rank test P < 0.0001). The Cox model for pOS alone showed a 7-year index of prediction accuracy of 26.9, which increased to 29.5 when IBPI was added to pOS as a complementary prognostic tool. IBPI was also associated with the risk of serious infectious postoperative complications (P = 0.0094; noninfectious complications, P = 0.6463). NLR was an independent prognostic factor for OS in RPS. When combined into a prognostic index with hemoglobin, monocytes, and PLR, it serves as a readily available prognostic tool addressing tumor-related inflammation and helps in classifying RPS risk in addition to the Sarculator nomogram.
Tumor-Infiltrating Lymphocyte Therapy in Melanoma: Facts to the Future
Authors: Allison Betof Warner, Pippa G. Corrie, Omid Hamid
Journal: Clinical Cancer Research (2022)

Abstract Adoptive cell therapy with tumor-infiltrating lymphocytes (TIL) is gaining momentum and demonstrating durable responses in patients with advanced melanoma. Although increasingly considered as a treatment option for select patients with melanoma, TIL therapy is not yet approved by any regulatory agency. Pioneering studies with first-generation TIL therapy, undertaken before the advent of modern melanoma therapeutics, demonstrated clinical efficacy and remarkable long-term overall survival, reaching beyond 20 months for responding patients. TIL therapy is a multistep process of harvesting patient-specific tumor-resident T cells from tumors, ex vivo T-cell expansion, and re-infusion into the same patient after a lymphodepleting preparative regimen, with subsequent supportive IL2 administration. Objective response rates between 30% and 50% have consistently been observed in heavily pretreated patients with metastatic melanoma, including those who have progressed after modern immune checkpoint inhibitors and BRAF targeted agents, a population with high unmet medical need. Although significant strides have been made in modern TIL therapeutics, refinement strategies to optimize patient selection, enhance TIL production, and improve efficacy are being explored. Here, we review past and present experience, current challenges, practical considerations, and future aspirations in the evolution of TIL therapy for the treatment of melanoma as well as other solid tumors.
Public Engagement through Inclusive Deliberation: The Human Genome International Commission and Citizens’ Juries
Authors: Naomi Scheinerman
Journal: The American Journal of Bioethics (2022)

In this paper, I take seriously calls for public engagement in human genome editing decision-making by endorsing the convening of a "Citizens Jury" in conjunction with the International Commission on the Clinical Use of Human Germline Genome Editing's next summit scheduled for March 6–8, 2023. This institutional modification promises a more inclusive, deliberative, and impactful form of engagement than standard bioethics engagement opportunities, such as comment periods, by serving both normative and political purposes in the quest to offer moral guidance on gene editing. In examining evidence from the Australian Citizens' Jury on Genome Editing convened in 2021, I argue that Citizens' Juries should work in tandem with governing institutions to preserve the role of expertise while ensuring that the diverse views of the public are incorporated into their final reports as well. First, early inclusivity allows "the people" to hold agenda setting power through helping to set resource priorities. This also makes a downstream deliberative event, such as the called for Global Citizens' Assembly, both more likely to occur and more influential on policy. Second, Jury's diverse composition promises substantive contributions to the Commission's work. Third, Citizens' Juries could help to cultivate the Commission's trustworthiness.
Exposure-Response Analyses of Tremelimumab Monotherapy or in Combination with Durvalumab in Patients with Unresectable Hepatocellular Carcinoma
Authors: Xuyang Song, Robin Kate Kelley, Anis A. Khan, Nathan Standifer, Diansong Zhou, KyoungSoo Lim, Rajesh Krishna, Lu Liu, Kun Wang, Patricia McCoon, Alejandra Negro, Philip He, Megan Gibbs, John F. Kurland, Ghassan K. Abou-Alfa
Journal: Clinical Cancer Research (2022)

A novel single-dose regimen of 300 mg tremelimumab in combination with durvalumab [Single Tremelimumab Regular Interval Durvalumab (STRIDE)] has demonstrated a favorable benefit-risk profile in the phase I/II Study 22 (NCT02519348) and phase III HIMALAYA study (NCT03298451). This study evaluated the pharmacokinetics, exposure-response, and exposure-pharmacodynamics relationships of tremelimumab in patients with unresectable hepatocellular carcinoma (uHCC).
Elevated Methionine Flux Drives Pyroptosis Evasion in Persister Cancer Cells
Authors: Asmaa El-Kenawi, Anders Berglund, Veronica Estrella, Yonghong Zhang, Min Liu, Ryan M. Putney, Sean J. Yoder, Joseph Johnson, Joel Brown, Robert Gatenby
Journal: Cancer Research (2022)

Induction of cell death represents a primary goal of most anticancer treatments. Despite the efficacy of such approaches, a small population of "persisters" develop evasion strategies to therapy-induced cell death. While previous studies have identified mechanisms of resistance to apoptosis, the mechanisms by which persisters dampen other forms of cell death, such as pyroptosis, remain to be elucidated. Pyroptosis is a form of inflammatory cell death that involves formation of membrane pores, ion gradient imbalance, water inflow, and membrane rupture. Herein, we investigate mechanisms by which cancer persisters resist pyroptosis, survive, then proliferate in the presence of tyrosine kinase inhibitors (TKI). Lung, prostate, and esophageal cancer persister cells remaining after treatments exhibited several hallmarks indicative of pyroptosis resistance. The inflammatory attributes of persisters included chronic activation of inflammasome, STING, and type I interferons. Comprehensive metabolomic characterization uncovered that TKI-induced pyroptotic persisters display high methionine consumption and excessive taurine production. Elevated methionine flux or exogenous taurine preserved plasma membrane integrity via osmolyte-mediated effects. Increased dependency on methionine flux decreased the level of one carbon metabolism intermediate S-(5'-adenosyl)-L-homocysteine, a determinant of cell methylation capacity. The consequent increase in methylation potential induced DNA hypermethylation of genes regulating metal ion balance and intrinsic immune response. This enabled thwarting TKI resistance by using the hypomethylating agent decitabine. In summary, the evolution of resistance to pyroptosis can occur via a stepwise process of physical acclimation and epigenetic changes without existing or recurrent mutations.Methionine enables cancer cells to persist by evading pyroptotic osmotic lysis, which leads to genome-wide hypermethylation that allows persisters to gain proliferative advantages.
Roux-en-Y Gastric Bypass Increases Glycemic Excursions During Pregnancy and Postpartum: A Prospective Cohort Study
Authors: Louise L. Stentebjerg, Lene R. Madsen, René K. Støving, Lise Lotte T. Andersen, Christina A. Vinter, Claus B. Juhl, Dorte M. Jensen
Journal: Diabetes Care (2022)

OBJECTIVE Roux-en-Y gastric bypass (RYGB) and pregnancy markedly alter glucose metabolism, but evidence on glucose metabolism in pregnancy after RYGB is limited. Thus, the aims of the Bariatric Surgery and Consequences for Mother and Baby in Pregnancy study were to investigate interstitial glucose (IG) profiles during pregnancy, risk factors associated with hypoglycemia, and the association between fetal growth and hypoglycemia in pregnant women previously treated with RYGB, compared with control participants. RESEARCH DESIGN AND METHODS Twenty-three pregnant women with RYGB and 23 BMI- and parity-matched pregnant women (control group) were prospectively studied with continuous glucose monitoring in their first, second, and third trimesters, and 4 weeks postpartum. Time in range (TIR) was defined as time with an IG level of 3.5–7.8 mmol/L. RESULTS Women with RYGB were 4 years (interquartile range [IQR] 0–7) older than control participants. Pregnancies occurred 30 months (IQR 15–98) after RYGB, which induced a reduction in BMI from 45 kg/m2 (IQR 42–54) presurgery to 32 kg/m2 (IQR 27–39) prepregnancy. Women with RYGB spent decreased TIR (87.3–89.5% vs. 93.3–96.1%; P &amp;lt; 0.01) owing to an approximately twofold increased time above range and increased time below range (TBR) throughout pregnancy and postpartum compared with control participants. Women with increased TBR had a longer surgery-to-conception interval, lower nadir weight, and greater weight loss after RYGB. Finally, women giving birth to small-for-gestational age neonates experienced slightly increased TBR. CONCLUSIONS Women with RYGB were more exposed to hypoglycemia and hyperglycemia during pregnancy compared with control participants. Further research should investigate whether hypoglycemia during pregnancy in women with RYGB is associated with decreased fetal growth.
Ventilator-induced Lung Injury Is Modulated by the Circadian Clock
Authors: Matthias Felten, Sebastian Ferencik, Luiz-Gustavo Teixeira Alves, Eleftheria Letsiou, Jasmin Lienau, Holger C. Müller-Redetzky, Alina Katharina Langenhagen, Anne Voß, Kristina Dietert, Olivia Kershaw, Achim D. Gruber, Laura Michalick, Wolfgang M. Kuebler, Bharath Ananthasubramaniam, Bert Maier, Henriette Uhlenhaut, Achim Kramer, Martin Witzenrath
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: Mechanical ventilation (MV) is life-saving but may evoke ventilator-induced lung injury (VILI). Objectives: To explore how the circadian clock modulates severity of murine VILI via the core clock component BMAL1 (basic helix-loop-helix ARNT like 1) in myeloid cells. Methods: Myeloid cell BMAL1-deficient (LysM (lysozyme 2 promoter/enhancer driving cre recombinase expression)Bmal1-/-) or wild-type control (LysMBmal1+/+) mice were subjected to 4 hours MV (34 ml/kg body weight) to induce lung injury. Ventilation was initiated at dawn or dusk or in complete darkness (circadian time [CT] 0 or CT12) to determine diurnal and circadian effects. Lung injury was quantified by lung function, pulmonary permeability, blood gas analysis, neutrophil recruitment, inflammatory markers, and histology. Neutrophil activation and oxidative burst were analyzed ex vivo. Measurements and Main Results: In diurnal experiments, mice ventilated at dawn exhibited higher permeability and neutrophil recruitment compared with dusk. Experiments at CT showed deterioration of pulmonary function, worsening of oxygenation, and increased mortality at CT0 compared with CT12. Wild-type neutrophils isolated at dawn showed higher activation and reactive oxygen species production compared with dusk, whereas these day-night differences were dampened in LysMBmal1-/- neutrophils. In LysMBmal1-/- mice, circadian variations in VILI severity were dampened and VILI-induced mortality at CT0 was reduced compared with LysMBmal1+/+ mice. Conclusions: Inflammatory response and lung barrier dysfunction upon MV exhibit diurnal variations, regulated by the circadian clock. LysMBmal1-/- mice are less susceptible to ventilation-induced pathology and lack circadian variation of severity compared with LysMBmal1+/+ mice. Our data suggest that the internal clock in myeloid cells is an important modulator of VILI.
Cardiopulmonary Pathogenic Networks: Unveiling the Gut–Lung Microbiome Axis in Pulmonary Arterial Hypertension
Authors: Suellen Darc Oliveira
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

"Cardiopulmonary Pathogenic Networks: Unveiling the Gut-Lung Microbiome Axis in Pulmonary Arterial Hypertension." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp. –
Associations Between New York Heart Association Classification, Objective Measures, and Long-term Prognosis in Mild Heart Failure
Authors: Luis E. Rohde, André Zimerman, Muthiah Vaduganathan, Brian L. Claggett, Milton Packer, Akshay S. Desai, Michael Zile, Jean Rouleau, Karl Swedberg, Martin Lefkowitz, Victor Shi, John J. V. McMurray, Scott D. Solomon
Journal: JAMA Cardiology (2022)

Heart failure (HF) treatment recommendations are centered on New York Heart Association (NYHA) classification, such that most apparently asymptomatic patients are not eligible for disease-modifying therapies.To assess within-patient variation in NYHA classification over time, the association between NYHA class and an objective measure of HF severity (N-terminal pro-B-type natriuretic peptide [NT-proBNP] level), and their association with long-term prognosis in the PARADIGM-HF trial.All patients in PARADIGM-HF were in NYHA class II or higher at baseline and were treated with sacubitril-valsartan during a 6- to 10-week run-in period before randomization. Patients classified as NYHA class I, II, and III in PARADIGM-HF were compared at randomization.NYHA class at randomization after 6 to 10 weeks of the run-in period.Primary outcome was cardiovascular death or first HF hospitalization. Logistic regression models, areas under the receiver operating characteristic curve (AUC), kernel density estimation overlaps, and Cox proportional hazards models were used.The analysis included 8326 patients with known NYHA classification at randomization. Of 389 patients in NYHA class I, 228 (58%) changed functional class during the first year after randomization. Level of NT-proBNP was a poor discriminator of NYHA classification: for NYHA class I vs II, the AUC was 0.51 (95% CI, 0.48-0.54). For NT-proBNP level, estimated kernel density overlap was 93% between NYHA class I vs II, 79% between NYHA I vs III, and 83% between NYHA II vs III. Patients classified as NYHA III displayed a distinctively higher rate of cardiovascular events (NYHA III vs I, hazard ratio [HR], 1.84; 95% CI, 1.44-2.37; NYHA III vs II, HR, 1.49; 95% CI, 1.35-1.64). Patients in NYHA class I and II revealed lower event rates (NYHA II vs I, HR, 1.24; 95% CI, 0.97-1.58). Stratification by NT-proBNP level (<1600 pg/mL or ≥1600 pg/mL) identified subgroups with distinctive risk, such that NYHA class I patients with high NT-proBNP levels (n = 175) had a numerically higher event rate than patients with low NT-proBNP levels from any NYHA class (vs I, HR, 3.43; 95% CI, 2.03-5.87; vs II, HR, 2.12; 95% CI, 1.58-2.86; vs III, HR, 1.37; 95% CI, 1.00-1.88).In this study, patients in NYHA class I and II overlapped substantially in objective measures and long-term prognosis. Physician-defined "asymptomatic" functional class concealed patients who were at substantial risk for adverse outcomes. NYHA classification might be limited to differentiate mild forms of HF.ClinicalTrials.gov Identifier: NCT01035255.
Mitochondrial dysfunction in macrophages promotes inflammation and suppresses repair after myocardial infarction
Authors: Shanshan Cai, Mingyue Zhao, Bo Zhou, Akira Yoshii, Darrian Bugg, Outi Villet, Anita Sahu, Gregory S. Olson, Jennifer Davis, Rong Tian
Journal: Journal of Clinical Investigation (2022)

Innate immune cells play important roles in tissue injury and repair following acute myocardial infarction (MI). Although reprogramming of macrophage metabolism has been observed during inflammation and resolution phases, the mechanistic link to macrophage phenotype is not fully understood. In this study, we found that myeloid-specific deletion (mKO) of mitochondrial complex I protein, encoded by Ndufs4, reproduced the proinflammatory metabolic profile in macrophages and exaggerated the response to LPS. Moreover, mKO mice showed increased mortality, poor scar formation, and worsened cardiac function 30 days after MI. We observed a greater inflammatory response in mKO mice on day 1 followed by increased cell death of infiltrating macrophages and blunted transition to the reparative phase during post-MI days 3-7. Efferocytosis was impaired in mKO macrophages, leading to lower expression of antiinflammatory cytokines and tissue repair factors, which suppressed the proliferation and activation of myofibroblasts in the infarcted area. Mitochondria-targeted ROS scavenging rescued these impairments, improved myofibroblast function in vivo, and reduced post-MI mortality in mKO mice. Together these results reveal a critical role of mitochondria in inflammation resolution and tissue repair via modulation of efferocytosis and crosstalk with fibroblasts. These findings have potential significance for post-MI recovery as well as for other inflammatory conditions.
Aerobic Exercise Training Response in Preterm-Born Young Adults with Elevated Blood Pressure and Stage 1 Hypertension: A Randomized Clinical Trial
Authors: Holger Burchert, Winok Lapidaire, Wilby Williamson, Annabelle McCourt, Cameron Dockerill, William Woodward, Cheryl M. J. Tan, Mariane Bertagnolli, Afifah Mohamed, Maryam Alsharqi, Henner Hanssen, Odaro J. Huckstep, Paul Leeson, Adam J. Lewandowski
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Premature birth is an independent predictor of long-term cardiovascular risk. Individuals affected are reported to have a lower rate of [Formula: see text]o